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Abstract Background Glioblastoma multiforme (GBM) is nowadays the most aggressive tumor affecting brain in adults with a very poor prognosis due to the limited therapies and the systemic cytotoxicity. Among the different new drugs, recently has been reported the in vitro anti-glioma activity of a new cationic platinum(II) complex bearing 8-aminoquinoline as chelating ligand (Pt-8AQ). The purpose of this research work was to confirm the activity of Pt-8AQ on U87-GM spheroid and to investigate the ability of Mesenchymal Stromal Cells (MSCs) to incorporate and release Pt-8AQ in its active form. The MSCs were primed with Pt-8AQ under optimized conditions and the secretome was analyzed for evaluating the cytotoxic activity of Pt-8AQ and the presence of Extracellular Vesicles (Evs). Results The principal results showed that Pt-8AQ incorporated by MSCs was released in the secretome and exerted a significant higher anticancer activity with respect to the free drug. The release of Pt-8AQ did not occur in Evs, as demonstrated for other drugs, but it could be delivered bound to some specific carriers able to enhance its bioavailability and efficacy. Some hypotheses are discussed to explain this surprisingly finding out that, however, it needs more investigations. Conclusions The major conclusions are that cell mediated drug delivery systems could provide a potential approach to facilitate the GBM therapy by intra-tumoral administration of cells loaded with Pt-8AQ, being MSCs able to integrate it into the tumor mass and exert high therapeutic efficacy in situ. The increased efficacy of Pt-8AQ delivered by MSCs even suggests to deeper investigate a possible direct use of MSCs secretome both in situ and/or by systemic administration, being secretome able to pass the blood–brain tumor.

Adipose tissue is mainly composed by adipocytes. Moreover, mesenchymal stromal/stem cells (MSCs), macrophages, endothelial cells, and extracellular matrix components are present. The variety of molecules as cytokines and growth factors of its structure very rich in blood vessel makes it also similar to a true endocrine organ that however needs still to be fully investigated. In our study, we used human lipoaspirate to obtain mechanically microfragmented fat (MiFAT) which was washed and then devitalized by freezing–thawing cycles. In our experiments, thawed MiFAT was used to stimulate cultures of MSCs from two different sources (adipose tissue and gingiva papilla) in comparison with a traditional stimulation in vitro obtained by culturing MSCs with adipogenic medium. MSCs stimulated with MiFAT showed a very early production of lipid droplets, after only 3 days, that correlated with an increased expression of adipokines. Furthermore, a significant upregulation of PPAR gamma 1 alpha coactivator (PPARGC1A) was observed with an overexpression of uncoupling protein 1 (UCP1) that suggest a pattern of differentiation compatible with the beige–brown fat.

Many patients report symptoms after wheat ingestion experiencing a wide spectrum of clinical manifestations. Three possible diagnoses have been recognized: celiac disease (CD), wheat allergy (WA), and non-celiac (gluten) wheat sensitivity (NCGS/NCWS). CD is a chronic immune-mediated disease of the small bowel caused by exposure to dietary gluten in genetically predisposed individuals, with a prevalence of approximately 1%. It is characterized by mucosal inflammation and atrophy following exposure to gluten and improvement after gluten withdrawal. Food allergies are immunological responses to a food antigen. WA is the expression of an immunologically mediated process that can be immunoglobulin E (IgE) or non-IgE mediated; its many symptoms include urticaria/angioedema, asthma, rhinitis, and anaphylaxis. NCGS/NCWS is characterized by gastrointestinal and/or extra-intestinal symptoms after ingestion of gluten-containing food in subjects not affected by CD or WA. The aim of this review is to help physicians and nutritionists diagnose the cause of symptoms reported after wheat ingestion, thus avoiding patient frustration, inappropriate testing, and incorrect or missed diagnoses. An algorithm for the diagnostic approach in these patients is provided, to help to diagnose CD, WA, NCGS/NCWS or to identify possible functional disorders as the wheat-sensitive irritable bowel syndrome. A personalized approach, regular follow-up, and the help of a skilled healthcare professional are mandatory for patients with symptoms following wheat ingestion is provided. A gluten-free-diet is often recommended for patients with self-reported gluten/wheat-dependent symptoms; for patients with symptoms similar to those of functional diseases while there is evidence that a low-FODMAP diet could be the first option.

Abstract The outbreak of COVID-19 and SARS-CoV-2 infection is spreading worldwide as the first coronavirus pandemic. The clinical picture is variable but flu-like symptoms are common with bilateral interstitial pneumonia being the most frightening presentation. No specific therapies nor vaccine have been developed to date and the only way to limit the virus diffusion is by modifying one’s lifestyle limiting social life and following strict hygienic precautions. No data is available on the risk of COVID-19 and its outcomes in celiac disease (CeD). The restrictions applied to counter COVID-19 can impact on CeD treatment and gluten-free dieting, the only available therapy for CeD. With the present manuscript, we aim to support gastroenterologists and nutritionists in the management of CeD patients in the new pandemic scenario, being conscious that availability and local situations are extremely various.

Abstract Background Gluten-free diet (GFD) decreases the quality of life of celiac disease (CD) patients, who frequently ask to occasionally ingest gluten-containing food. We evaluated CD patients reporting voluntary and occasional transgressions to their GFD. Methods From October 2017 to September 2018, the patients reporting occasional and voluntary gluten ingestion (GFD-noncompliant) were prospectively enrolled. These patients underwent clinical examination, blood tests, duodenal biopsy, capsule enteroscopy (CE), and a validated food-frequency questionnaire (FFQ) assessing the frequency and quantity of gluten intake. Mortality was calculated and compared to the general population. A group of patients on strict GFD (GFD-adherent) acted as controls. Results One thousand three hundred seventy-eight CD patients were evaluated during the study period. One hundred nine (8%) reported occasional (weekly or monthly) voluntary ingestion of gluten. The mean gluten intake was 185.2 ± 336.9 g/year, and the duration of their incorrect GFD was 8.6 ± 6.9 years. Among the noncompliant patients, 57% did not present any histological alteration; furthermore, the Marsh score profile was not different between compliant and noncompliant patients. Seventy percent did not present any alteration at CE. Seventy-five percent of patients reported no gastrointestinal symptoms after gluten ingestion. Twenty-three percent of patients in the GFD-noncompliant group presented positive tTG-IgA. No association was found between gluten intake, clinical symptoms, and biomarkers. Mortality was not different between the groups and the general population. Conclusions Our results are that in a real-life scenario, a group of CD patients on long-term gluten intake showed no significant clinical symptoms or small bowel damage, thus suggesting that a degree of tolerance towards gluten consumption can be reached.

Background: The introduction of telemedicine into gastroenterology practice has been a major change over the past decade. Particularly during the COVID-19 pandemic, it has been very helpful for patients with chronic gastrointestinal disease as it has allowed continued healthcare delivery. Patient acceptance of televisits is key for its implementation in usual clinical practice, but lack of patient trust may limit its adoption. During the COVID-19 pandemic, we have embraced televisits instead of the traditional in-person medical examinations.The aim of the study was to evaluate the feasibility of televisits and factors influencing patient trust. Methods: Patient trust in televisits was assessed through a validated questionnaire (PATAT). We employed machine learning (decision trees and random forests) in order to clearly understand the relationships between covariates influencing patient trust. Results: Most televisits were successfully performed (186/218, 86.2%) and highly trusted (155/163, 95.2%). According to the decision tree, ‘The video service is easy to use’ in the parent node had the most influence on patient trust. Trust in the care organization, in the treatment, and in guaranteed data protection policies were the other factors influencing patient trust. In the random forest analysis, the use of known and user-friendly video services (12.8%IncMSE) and confidence in the data protection policies (12.4%IncMSE) were the two variables contributing most to trust in televisits. Conclusion: Most patients with chronic gastrointestinal disease agreed to receive a televisit and trusted it. Knowledge of factors determining patient trust is essential to improve patient–doctor communication in order to increase the use of telemedicine in gastroenterology.

(1) Background: The identification of vaccination status and attitudes towards vaccines among celiac disease (CD) patients is of great importance, but it has not yet been investigated. The aim of this study was to investigate coverage against vaccine-preventable diseases (VPDs), attitudes towards vaccinations, and its determinants among CD patients. (2) Methods: An anonymous web-based validated questionnaire was sent to a mailing list of CD adult patients. Patients were asked to self-report their previous vaccinations and attitudes towards vaccinations, which were defined as positive, negative, and partially positive/negative. The influencing factors towards vaccinations were investigated, and crude and adjusted odds ratios (AdjORs) with 95% confidence intervals (CIs) were calculated. (3) Results: The questionnaire was sent to 412 patients, with a response rate of 31.6% (130 patients, 105 women, median age 40 years, interquartile range 36–51). Patients self-reported vaccination against the following diseases: 73.8% tetanus, 42.3% flu, 20% measles, mumps and rubella, 19.2% meningitis, and 16.2% pneumococcus. Thirty-two people (24.6%) did not remember all of their previous vaccinations. In total, 104 (80%) respondents had a positive attitude towards vaccines, 25 (19.2%) a partially positive/negative one, and 1 a negative one. The determinants significantly influencing the positive attitude were being a graduate (AdjORs 7.49) and a belief in the possible return of VPDs with declining vaccination coverage rates (AdjORs 7.42), while the use of complementary and alternative medicines (AdjORs 0.11) and past negative experience (AdjORs 0.16) were associated with a negative attitude. (4) Conclusions: Despite four out of five CD patients showing a strong positive attitude towards vaccinations, one out of five had a partially negative one. Only a minority (16–20%) reported being vaccinated against some VPDs potentially harmful to their CD because of hyposplenism, such as meningitis and pneumococcus. The low vaccination rate against some VPDs, in spite of the 80% of CD patients stating a positive attitude towards vaccination, may be explained in part by patients’ vaccine hesitancy and in part by a possible role of physicians in under-prescribing vaccinations to these patients. These results may be a starting point for developing specific vaccination campaigns to increase vaccination rates against VPDs in CD patients.

Despite following a gluten-free diet, which is currently the only effective therapy for celiac disease, about 5% of patients can develop serious complications, which in the case of refractory type 2 could evolve towards intestinal lymphoma. In this study, we have identified a set of 15 microRNAs in serum discriminating between the two types of refractory disease. Upregulated miR-770-5p, miR-181b-2-3p, miR-1193, and miR-1226-3p could be useful for the better stratification of patients and the monitoring of disease development, while miR-490-3p was found to be dysregulated in patients with refractory type 1. Finally, by using bioinformatic tools applied to the analysis of the targets of dysregulated microRNAs, we have completed a more precise assessment of their functions. These mainly include the pathway of response to Transforming Growth Factor β cell–cell signaling by Wnt; epigenetic regulation, especially novel networks associated with transcriptional and post-transcriptional alterations; and the well-known inflammatory profiles.

Gluten-free diet (GFD) is the current treatment of gluten-related disorders. It eliminates wheat, barley, and rye, while the exclusion of oats is still under debate. GFD is based on a combination of naturally gluten-free foods and gluten-free substitutes of cereal-based foods. Although effective as treatment of gluten-related disorders, today there is concern about how to improve GFD's nutritional quality, to make it not only gluten-free, but also healthy. The “Mediterranean diet” (MedD) refers to the dietary pattern and eating habits typical of populations living in the Mediterranean basin, which have been associated with low prevalence of several diet-related pathologies. Here we present a narrative review of the current knowledge about GFD and MedD, their characteristics and central food components. Based on the Mediterranean diet pyramid developed by the Italian pediatric society, we propose a combination between the MedD and the GFD, an attractive alternative to reach a gluten-free state that at the same time is healthy, with a clear benefit to those who practice it.

The gluten-free diet (GFD) is a restrictive diet. In many cases, it must be permanent and strict, and it may be associated with both nutritional deficiencies and excesses, which can be prevented by following a healthy, natural Mediterranean GFD (Med-GFD). In this paper, we describe the importance of the Mediterranean diet, the correct intake of vitamins and minerals, and how they may play an important protective role against chronic or degenerative conditions. Herewith, we analyze different aspects that influence the ability to maintain a correct and balanced Med-GFD, which may contribute to the health status of patients, including a conscious use of gluten-free products to maintain a healthy lifestyle. Monitoring the Med-GFD remains a pivotal issue: to evaluate the presence of gluten peptides in urine, it could be important to introduce point-of-care testing, an efficient method for GFD self-monitoring (immunochromatographic technique), together with online nutritional questionnaires. Indeed, medical care via telemedicine can provide practical indications aimed at supporting patients and doctors. A natural Med-GFD can ensure the correct intake of nutrients and could be important for patients affected by gluten-related disorders, helping them to maintain a correct and healthy lifestyle.

(1) Background: COVID-19 vaccination campaigns offer the best hope of controlling the pandemic. However, the fast production of COVID-19 vaccines has caused concern among the general public regarding their safety and efficacy. In particular, patients with chronic illnesses, such as celiac disease (CD), may be more fearful. Information on vaccine hesitancy plays a pivotal role in the development of an efficient vaccination campaign. In our study, we aimed to evaluate COVID-19 vaccine hesitancy among Italian CD patients. (2) Methods: an anonymous questionnaire was sent to CD patients followed at our tertiary referral center for CD in Milan, Italy. Patients were defined as willing, hesitant and refusing. We evaluated the reasons for hesitancy/refusal and the possible determinants, calculating crude and adjusted odds ratios [AdjORs] with 95% confidence intervals [CIs]. (3) Results: the questionnaire was sent to 346 patients with a response rate of 29.8%. Twenty-six (25.2%) of the 103 respondents were hesitant, with a total refusal rate of 4.8%. The main reason was fear of adverse events related to vaccination (68.2%). Among hesitant patients, 23% declared that their opinion was influenced by their CD. The determinants positively influencing willingness to be vaccinated against COVID-19 were adherence to a GFD, perception of good knowledge about COVID-19 and its vaccines, and a positive attitude to previous vaccines (AdjOR 12.71, 95% CI 1.82–88.58, AdjOR 6.50, 95% CI 1.44–29.22, AdjOR 0.70, 95% CI 0.11–4.34, respectively). (4) Conclusions: CD patients should be vaccinated against COVID-19 and a specific campaign to address the determinants of hesitancy should be developed.

Epithelial-to-Mesenchymal Transition (EMT) is relevant in malignant growth and frequently correlates with worsening disease progression due to its implications in metastases and resistance to therapeutic interventions. Although EMT is known to occur in several types of solid tumors, the information concerning tumors arising from the epithelia of the bile tract is still limited. In order to approach the problem of EMT in cholangiocarcinoma, we decided to investigate the changes in protein expression occurring in two cell lines under conditions leading to growth as adherent monolayers or to formation of multicellular tumor spheroids (MCTS), which are considered culture models that better mimic the growth characteristics of in-vivo solid tumors. In our system, changes in phenotypes occur with only a decrease in transmembrane E-cadherin and vimentin expression, minor changes in the transglutaminase protein/activity but with significant differences in the proteome profiles, with declining and increasing expression in 6 and in 16 proteins identified by mass spectrometry. The arising protein patterns were analyzed based on canonical pathways and network analysis. These results suggest that significant metabolic rearrangements occur during the conversion of cholangiocarcinomas cells to the MCTS phenotype, which most likely affect the carbohydrate metabolism, protein folding, cytoskeletal activity, and tissue sensitivity to oxygen.

Urinary biomarkers of mycotoxin exposure were evaluated in a group of celiac patients (n = 55) and in a control group of healthy subjects (n = 50) following their habitual diet. Deoxynivalenol (DON), zearalenone (ZEN), and fumonisin B1 (FB1) were monitored in 105 urinary samples collected from the two groups. Dietary habits were also recorded through compilation of a seven-day weighed dietary diary. Biomarkers of mycotoxin exposure were detected in 21 celiac patients and in 15 control subjects, corresponding to about 34% of total participants. In particular, ZEN was the most detected mycotoxin among all the studied subjects with a total of 19 positive cases. Results did not show a statistically significant difference in mycotoxin exposure between the two groups, and the presence of specific mycotoxins was not related to the intake of any particular food category. Our findings suggest little urgency of specific regulation for gluten free products, although the prevalence of exposure observed in free-living diets of both celiac and healthy subjects underlines the need of a constant surveillance on mycotoxins occurrence at large.

Abstract   Background The significance of the presence of anti-gliadin antibodies in patients affected by celiac disease is still unclear. It is hypothesized that gliadin deamidation, catalysed by transglutaminase, plays a role in favoring the antigen presentation. Aim To determine the immunoreactivity of anti-gliadin antibodies from untreated celiac patients to transglutaminase deamidated gliadins. Materials and methods Gliadins from wheat flour underwent enzymatic digestion and were deamidated or cysteamine-transamidated by transglutaminase. Immunoreactivity of anti-gliadin antibodies from untreated adult celiac patients sera was evaluated by means of a competitive enzyme-linked immunosorbent assay (ELISA) method. Results Gliadin deamidation increased antibodies immunoreactivity from 25% to 50% while cysteamine incorporation into the gliadin peptides resulted in an immunoreactivity decrease. Conclusions Increased immunoreactivity of transglutaminase deamidated gliadins tested with anti-gliadin antibodies from untreated adult celiac patients supports the hypothesis of a pivotal role of gliadin deamidation in the pathomechanism of celiac disease. [ABSTRACT FROM AUTHOR]